Tauopathies are conditions in which accumulation of tau into neurofibrillary tangles causes dysfunction and cell death in the brain. Alzheimer's disease is the best known of these neurodegenerative conditions. Researchers here demonstrate an approach to reducing both tau aggregation and inflammation in mice, based on inhibition of leukotrienes. Mouse models of neurodegenerative conditions based on protein aggregation are highly artificial, as these forms of aggregation do not naturally occur in that species. This can produce misleading results, or at least results that have to be carefully assessed in the full understanding of the biochemistry involved, and how it might differ from that of humans. That said, the approach here does use an established pharmaceutical compound, meaning that there is a comparatively short path towards validation of the mechanism in human patients.
Researchers have shown, for the first time in an animal model, that tau pathology - the second-most important lesion in the brain in patients with Alzheimer's disease - can be reversed by a drug. The researchers landed on their breakthrough after discovering that inflammatory molecules known as leukotrienes are deregulated in Alzheimer's disease and related dementias. In experiments in animals, they found that the leukotriene pathway plays an especially important role in the later stages of disease. "At the onset of dementia, leukotrienes attempt to protect nerve cells, but over the long term, they cause damage. Having discovered this, we wanted to know whether blocking leukotrienes could reverse the damage, whether we could do something to fix memory and learning impairments in mice having already abundant tau pathology."
To recapitulate the clinical situation of dementia in humans, in which patients are already symptomatic by the time they are diagnosed, researchers used specially engineered tau transgenic mice, which develop tau pathology - characterized by neurofibrillary tangles, disrupted synapses (the junctions between neurons that allow them to communicate with one another), and declines in memory and learning ability - as they age. When the animals were 12 months old, the equivalent of age 60 in humans, they were treated with zileuton, a drug that inhibits leukotriene formation by blocking the 5-lipoxygenase enzyme. After 16 weeks of treatment, animals were administered maze tests to assess their working memory and their spatial learning memory. Compared with untreated animals, tau mice that had received zileuton performed significantly better on the tests. Their superior performance suggested a successful reversal of memory deficiency.
To determine why this happened, the researchers first analyzed leukotriene levels. They found that treated tau mice experienced a 90-percent reduction in leukotrienes compared with untreated mice. In addition, levels of phosphorylated and insoluble tau, the form of the protein that is known to directly damage synapses, were 50 percent lower in treated animals. Microscopic examination revealed vast differences in synaptic integrity between the groups of mice. Whereas untreated animals had severe synaptic deterioration, the synapses of treated tau animals were indistinguishable from those of ordinary mice without the disease. "Inflammation was completely gone from tau mice treated with the drug. The therapy shut down inflammatory processes in the brain, allowing the tau damage to be reversed."